Successful allogeneic hematopoietic cell transplantation (HCT) requires lymphopoietic recovery, control of graft vs. host disease (GVHD), and protection against relapse. Exploitationof NK cell reactivity requires understanding NK cell regulation through class I recognizing, killer immunoglohulin-like receptors (KIR) and algorithms for donor choice to maximize donor NK cell reactivity. We propose prospective clinical trials and analyses to target this reactivity. Aim 1 will investigate KIR-ligand mismatched unrelated donor(URD) HCT of a partiallyT-cell depleted matched graft to control GVHD and enhance anti-leukemia effects. Acquisition of NK cells which escape alloinhibition (through inhibitory KIR) may improve outcome. In Aim 2, 2 prospective analyses will test NK cell:KIR functional interaction on HCT outcome. In Aim 2a, we hypothesize that an activating KIR genotype and recovery of normal, donor pattern KIR expression will better protect against infection. Donor and recipient KIR genotype may predict infection risk. Aim 2b will prospectively evaluate differences in KIR genotype and expression in a prospective randomized trial of URD blood vs. bone marrow HCT. Donor and recipient KIR difference and expression will be tested for effects on risk of GVHD, infections, and relapse; differentiallyin PB or BM grafts. We will test 4 strategies for NK & KIR matching on outcome. The first two strategies depend only on HLA class I phenotype: 1) KIR-ligand mismatch; 2) recipient KIR-ligand absence; using KIR genotyping in 3) recipient KIR-ligand: donor KIR gene cor tent; and using both KIR genotyping and expression on NK cells, 4) recipient KIR-ligand: recipient donor-derived KIR expression. Each may clarify the physiologic regulation of NK:host interaction. Aim 3 will extend our work using haploidentical donor NK infusions in a clinical trial testing donor NK cells in a reduced intensity HCT. Donor NK infusions may deplete recipient dendritic cells, limit GVHD and aid in prevention of relapse. These studies, using KIR genotype and KIR expression data developed in Projects 1 and 2, will explore the clinical applicability of NK alloreactivity to improve the success; of allogeneic HCT.